This invention relates to chemotherapeutic agents that are preferably non-lethal, non-corrosive, and/or non-irritating to the recipient, and preferably can cause apoptosis. The present invention can be employed as a chemotherapeutic agent for both solid and disseminated tumors.
The oligodynamic action or the antimicrobial activity of small amounts of metal has been known for a long time and is the basis for the development of many metal coordination complexes therapeutic agents. In fact, metal ions such as mercury (II), cadmium (II), zinc (II), germanium (II), copper (II), and silver (I) ions have been used for the treatment of many infectious diseases (Merluzzi, V. J., et al., Research Communications in Chemical Path. Pharmacol., 66, 425 (1989); Slawson, R. M., et al., Plasmid, 27, 72 (1992); Khurshid, H. Pak. J. Pharmacol. 13, 41 (1996); Klasen, H. J. Burns, 26, 131 (2000); Dibrov, P., et al., A.A.C., 46, 2668 (2002); Richard (III), J. W., et al., J. Burns and Surg. Wound Care, 1, 11 (2002)).
Besides the use of heavy metals as antibiotic agents, they are also employed in the design of chemotherapeutic compounds. The current treatments for cell proliferative diseases such as cancer employ metal coordination complexes where such complexes inhibit DNA replication and cell division. The most prominent and promising family of cytotoxic agents that has proved to have clinical benefits is one that uses platinum as the heavy metal (Pil, P., & Lippard, S. in Encyclopedia of Cancer, ed. Bertino, J. R. (Academic Press, San Diego), pp. 392-410 (1997); Jakupec, M., et al., Rev. Physiol. Biochem. Pharmacol., 146, 1 (2003)). One of the most active and broad-spectrum chemotherapeutic drugs belonging to this family is cisplatin, cis-diaminedichloroplatinum (II), which is used to treat epithelial malignancies such as testicular cancer and ovarian carcinoma (Pil, P., & Lippard, S. in Encyclopedia of Cancer, ed. Bertino, J. R. (Academic Press, San Diego), pp. 392-410 (1997); Jakupec, M., et al., Rev. Physiol. Biochem. Pharmacol., 146, 1 (2003)). Following its serendipitous discovery as an antitumor drug, other useful chemotherapeutic drugs that employ platinum such as carboplatin were also developed (Pil, P., & Lippard, S. in Encyclopedia of Cancer, ed. Bertino, J. R. (Academic Press, San Diego), pp. 392-410 (1997)). With this growing interest, other metal coordination complexes have been explored. Examples of such metals are gold, titanium, copper, iridium, and rhodium (Haiduc, I., & Silvestru, C. In Vivo, 3, 285 (1989); Caruso, F., et al., J. Med. Chem., 43, 3665-(2000); Caruso, F., et al., J. Med. Chem., 46, 1737 (2003)).
Ionic silver substances are resurging again in popularity due to the fact that silver at low concentrations has no toxicity, mutagenicity or carcinogenic activities, and exhibits an excellent clinical tolerance compared to other metals (Furst, A, & Schlauder, M. J. Environ. Pathol. Toxicol., 1, 51 (1978); Pedahzur, R., et al., Wat. Sci. Tech., 31, 123 (1995); Demerec, M., et al., Am. Nat., 85, 119 (1951); Rossman, T. G., & Molina, M. Environ. Mutagen., 8, 263 (1986); Nishioka, H. Mutat. Res., 31, 185 (1987)). Additionally, ubiquitous metallothioneins, which are present in all living organisms, have the property of binding silver and other metals in metal thiolate cluster structures to transport, store, and detoxify essential and nonessential trace metals that may enter the body (Stillman, M. J., et al., Metal-Based Drugs, 1, 375 (1994)).
The quantity of silver administered and its chemical form determine the distribution of silver to various body tissues. Once absorbed, silver undergoes a first-pass effect through the liver, and is secreted into the bile, reducing the systemic distribution to tissues (ATSDR. (1990) Toxicological profile for silver), available online at wwwdotatsdrdotcdcdotgov/toxprofiles/tp146-pdotpdf. The only known condition that results from chronic exposure to high levels of silver for a prolonged period of time in humans is argyria, a benign condition which results in permanent bluish-gray discoloration of the skin. The only clinical effect observed with argyria is an aesthetic effect and there are no pathological changes or inflammatory reactions resulting from silver deposition (IRIS. (1987) Silver.), available online at wwwdotepadotgov/iris/subst/0099dothtm. Based on patients receiving i.v. injections of silver arsphenamine, the LOAEL (lowest-observed-adverse-effect level) for argyria was determined to be 0.014 mg/kg/day (IRIS. (1987) Silver. [Online.] wwwdotepadotgov/iris/subst/0099dothtm. (The above Internet addresses are altered to substitute “dot” for “.” so that the addresses as written are not executable as hyperlinks.)
U.S. patent application Ser. No. 10/867,214, filed Jun. 14, 2004 and incorporated herein in its entirety by reference, describes the use of organo-metallic complexes as chemotherapeutic agents and as anti-microbial agents. The technology described therein relates generally to the combination of two components. The first component is an organic (R) metal (M) complex (R-M), such as described in U.S. Pat. Nos. 6,242,009 and 6,630,172, incorporated in their entirety by reference herein. This R-M complex can be combined with a system for generating one or more reactive oxygen species (ROS) through the agency of reducing cofactors with the combination preferably producing a synergistic effect that can be highly effective in the destruction of microbes and/or cancerous or pre-cancerous cells. The composition can be prepared by mixing a metal salt compound in an aqueous solution, and an inorganic acid at room temperature to adjust the pH of the solution; adding an amino acid or potassium sodium tartrate in a specified amount with respect to the valency of the designated metal while homogenizing the mixture, and adding a ROS generating system. Depending on its use, the resultant solution can then be used either directly, or can be diluted with aqueous solutions such as distilled and/or deionized water to provide the necessary cytotoxicity and biocidal activities. The invention of U.S. patent application Ser. No. 10/867,214 can be prepared in any manner that produces an R-M complex in combination with an ROS. More specifically, the cited invention can be prepared by first preparing the R-M complex in any method described in U.S. Pat. Nos. 6,242,009 and 6,630,172, incorporated in their entirety by reference herein. The R part of the complex represents an amino acid such as isoleucine, phenylalanine, leucine, lysine, methionine, threonine, tryptophan, valine, alanine, glycine, arginine, histidine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, phenylalanine, proline, serine, tyrosine, or mixtures thereof or potassium sodium tartrate. With respect to the other part of the complex that is M, M represents at least one monovalent or polyvalent metal ion or cation, which is anticancerous and/or antimicrobial to at least one microorganism. Preferably, the metal ion is anticancerous and/or microbicidal to a multitude of microorganisms. Examples of the metal ion include, but are not limited to, cations of silver including colloidal silver, copper, zinc, mercury, manganese, chromium, nickel, cadmium, arsenic, cobalt, aluminum, lead, iron, rhodium, iridium, selenium, platinum, gold, titanium, tin, barium, bismuth, vanadium, iron, strontium, antimony, and salts thereof, and the like, and any combination thereof.
The rate of formation of ROS can be allowed to proceed unassisted or may be enhanced through the use of rate increasing agents, like compounds such as enzymes/co-enzymes or catalysts/co-factors. Generally, a coenzyme can contact and reduce a metal catalyst. The reduced metal catalyst may then function to facilitate the production of ROS from the ROS generating species, ordinarily through the donation of an electron. Any number of reducing cofactors/coenzymes may be used. More specifically, the coenzymes (reduced form shown), nicotinamide adenine dinucleotide (NADH), nicotinamide adenine dinucleotide phosphate (NADPH) and/or flavin adenine dinucleotide (FADH) are particularly effective as electron carriers. Similarly, any number of oxidizing metal catalysts/cofactors capable of generating ROS can be utilized. More specifically, Cu2+, Fe2+, Fe3+, K+, Mg2+, Mn2+, Mo, Ni2+, Se, and/or Zn2+ are particularly effective catalysts. These catalysts may be used in their pure form or may be combined with a salt and then be introduced into a solvent. One method of producing ROS can be through the breakdown of H2O2 (hydrogen peroxide) to form hydroxyl radicals.
The current treatments for cancer employ cytotoxic heavy metals, which inhibit cell division and DNA replication. Albeit various robust methods and techniques have been employed to combat cancer, there is a deluge of caveats and various difficulties associated with cancer therapy. Cancer therapy nowadays involves a multi-modality approach of a combination of chemotherapy, radiation, hormone therapy, immunotherapy, and antiangiogenic drugs. Surgery, on the other hand, involves the bulk removal of diseased tissue. While surgery is sometimes effective in removing solid tumors located at certain sites, for example, in the breast, colon, and skin, it cannot be used in the treatment of tumors located in other areas, such as the backbone, nor in the treatment of disseminated neoplastic conditions such as leukemia. If portions of the primary tumor cannot be removed or if it is believed to have metastasized, systemic drug therapy is given to kill residual cancerous cells through targeting of actively dividing cells.
There are difficulties associated with metal-based cancerous compounds in that effective treatment is hampered by lack of specificity and difficulty in delivering these agents to the site of the carcinogenic tumors. The lack of specificity of cytotoxic drugs for tumors cells and the resulting toxicity to normal tissue hampers an additional exploitation of their apoptotic effects. This is especially true with using hemotherapeutic and cytotoxic agents with solid neoplasms since within the inter region of neoplasmic cells, the network of blood capillaries is too small for such agents to be delivered (Jain, R. K. Cancer Metastasis Rev., 9, 253 (1990); Forbes, N. S., et al., Cancer Res., 63, 5188 (2003); Znati, C. A., et al., Clin. Cancer Res., 9, 5508 (2003); Jain, R. K. Nat. Med., 9, 685 (2003); Jain, R., & Booth, M. F. J. Clin. Invest., 112, 1134 (2003); Jain, R. K. in Clinical Oncology, eds. Abeloff, M., Armtage, J., Niederhuber, J., Kastan, M., McKenna, W., 3rd ed., (Elsevier, Philadelphia), pp. 153-172 (2004)). These regions commonly exist in most major classes of solid tumors such as those associated with breast, head and neck, pancreatic, stomach, ovarian, cervical, lung, and prostate tumors.
Adding to that is the problem of the patient developing a resistance with the continual, prolonged use of such agents. There is also a plethora of adverse side effects, some of which are irreversible, associated with cisplatin, including tubular necrosis, thrombocytopenia, anaemia, nausea, tinnitus, loss of sight, peripheral and autonomic neuropathies, urticaria, erythema, facial oedema, cytopenia, cachexia, alopecia, and angioedema, and many others related to pulmonary, reproductive and endocrine, and even cardiac arrest, especially at high doses (Slapak, C. A., & Kufe, D. W. in Harrison's Principles of Internal Medicine, ed. Isselbacker, K. J., 14th ed., (McGraw-Hill, New York), pp. 523-537 (1998); Sweetman, S. C. Martindale: the Complete Drug Reference, 3rd ed., (Pharmaceutical Press, London-Chicago), pp. 525-527 (2002)). These induced side effects significantly impact the quality of life of the patient and frequently dramatically influence the patient's compliance with the treatment regimen. These complications are the major dose-limiting toxicity and can lead to hospitalization of the patient and analgesics for the alleviation of pain.
In addition, new approaches are needed to overcome the two major overriding problems in the design of chemotherapeutic drugs; namely, the lack of selectivity of chemotherapeutic drugs in distinguishing normal and tumor cells, and the common occurrence of drug-resistant tumors. Cytotoxic drugs select only those cells that are able to withstand assault, while resistant cells remain unaffected. This as a result will eliminate the complete clinical effectiveness of the designated drug. Given the current state of affairs, there is an immediate need to develop cytotoxic drugs that can circumvent these obstacles. Therefore, central tenets in the design of such molecules are the control of toxicity and targeting of the metal to specific cancerous cells.
Accordingly, there is an immediate need to develop and design a new generation of chemotherapeutic agents that are able to overcome the above-described disadvantages.